Correcting mean-field approximations for birth-death-movement processes

On the microscale, migration, proliferation and death are crucial in the development, homeostasis and repair of an organism; on the macroscale, such effects are important in the sustainability of a population in its environment. Dependent on the relative rates of migration, proliferation and death, spatial heterogeneity may arise within an initially uniform field; this leads to the formation of spatial correlations and can have a negative impact upon population growth. Usually, such effects are neglected in modeling studies and simple phenomenological descriptions, such as the logistic model, are used to model population growth. In this work we outline some methods for analyzing exclusion processes which include agent proliferation, death and motility in two and three spatial dimensions with spatially homogeneous initial conditions. The mean-field description for these types of processes is of logistic form; we show that, under certain parameter conditions, such systems may display large deviations from the mean field, and suggest computationally tractable methods to correct the logistic-type description.

A chimeric vitronectin : IGF-I protein supports feeder-cell-free and serum-free culture of human embryonic stem cells

This paper was retracted by the Journal of Stem Cells and Development on February 15, 2013.

Death by Drowning : Gary Bryson's Turtle [A Review]

Accused of being autobiographical, as many debut novels often are, Turtle, upon first reading and further prying, does read as a story wrenched out of Gary Bryson’s own life. In a recent interview with Mandy Sayer, however, he was quick to deny all sorts of archetypal allegations. “Any resemblance to turtles living or dead”, Bryson explained, “is entirely coincidental”. Regardless of the many parallels that align author with protagonist—both were born and raised in a grey-skied Glasgow, both grew up in self-described dysfunctional families, and both returned to the colourless city to attend their mothers’ funerals—the narrative combines bruising black comedy with moments of magic realism. The result is an unlikely but often surprising concoction of twists and turns, each of which mixes the fallibility of memory with the slippery nature of truth. This playfulness between the material world and its metaphorical counterpart raises questions, not only about the curse that poisons its characters, but about the ethical implications of blurring fact and fiction...

Involvement of Exo1b in DNA damage-induced apoptosis

Apoptosis is essential for the maintenance of inherited genomic integrity. During DNA damage-induced apoptosis, mechanisms of cell survival, such as DNA repair are inactivated to allow cell death to proceed. Here, we describe a role for the mammalian DNA repair enzyme Exonuclease 1 (Exo1) in DNA damage-induced apoptosis. Depletion of Exo1 in human fibroblasts, or mouse embryonic fibroblasts led to a delay in DNA damage-induced apoptosis. Furthermore, we show that Exo1 acts upstream of caspase-3, DNA fragmentation and cytochrome c release. In addition, induction of apoptosis with DNA-damaging agents led to cleavage of both isoforms of Exo1. The cleavage of Exo1 was mapped to Asp514, and shown to be mediated by caspase-3. Expression of a caspase-3 cleavage site mutant form of Exo1, Asp514Ala, prevented formation of the previously observed fragment without any affect on the onset of apoptosis. We conclude that Exo1 has a role in the timely induction of apoptosis and that it is subsequently cleaved and degraded during apoptosis, potentially inhibiting DNA damage repair.

Mesenchymal stem cells

Cell based therapies as they apply to tissue engineering and regenerative medicine, require cells capable of self renewal and differentiation, and a prerequisite is to be able to prepare an effective dose of ex vivo expanded cells for autologous transplants. The in vivo identification of a source of physiologically relevant cell types suitable for cell therapies therefore figures as an integral part of tissue engineering. Stem cells serve as a reserve for biological repair, having the potential to differentiate into a number of specialised cell types within the body; they therefore represent the most useful candidates for cell based therapies. The primary goal of stem cell research is to produce cells that are both patient specific, as well as having properties suitable for the specific conditions for which they are intended to remedy. From a purely scientific perspective, stem cells allow scientists to gain a deeper understanding of developmental biology and regenerative therapies. Stem cells have acquired a number of uses for applications in regenerative medicine, immunotherapy, gene therapy, but it is in the area of tissue engineering that they generate most excitement, primarily as a result of their capacity for self-renewal and pluripotency. A unique feature of stem cells is their ability to maintain an uncommitted quiescent state in vivo and then, once triggered by conditions such as disease, injury or natural wear or tear, serve as a reservoir and natural support system to replenish lost cells. Although these cells retain the plasticity to differentiate into various tissues, being able to control this differentiation process is still one of the biggest challenges facing stem cell research. In an effort to harness the potential of these cells a number of studies have been conducted using both embryonic/foetal and adult stem cells. The use of embryonic stem cells (ESC) have been hampered by strong ethical and political concerns, this despite their perceived versatility due to their pluripotency. Ethical issues aside, other concerns raised with ESCs relates to the possibility of tumorigenesis, immune rejection and complications with immunosuppressive therapies, all of which adds layers of complications to the application ESC in research and which has led to the search for alternative sources for stem cells. The adult tissues in higher organisms harbours cells, termed adult stem cells, and these cells are reminiscent of unprogrammed stem cells. A number of sources of adult stem cells have been described. Bone marrow is by far the most accessible source of two potent populations of adult stem cells, namely haematopoietic stem cells (HSCs) and bone marrow mesenchymal stem cells (BMSCs). Autologously harvested adult stem cells can, in contrast to embryonic stem cells, readily be used in autografts, since immune rejection is not an issue; and their use in scientific research has not attracted the ethical concerns which have been the case with embryonic stem cells. The major limitation to their use, however, is the fact that adult stem cells are exceedingly rare in most tissues. This fact makes identifying and isolating these cells problematic; bone marrow being perhaps the only notable exception. Unlike the case of HSCs, there are as yet no rigorous criteria for characterizing MSCs. Changing acuity about the pluripotency of MSCs in recent studies has expanded their potential application; however, the underlying molecular pathways which impart the features distinctive to MSCs remain elusive. Furthermore, the sparse in vivo distribution of these cells imposes a clear limitation to their study in vitro. Also, when MSCs are cultured in vitro, there is a loss of the in vivo microenvironment, resulting in a progressive decline in proliferation potential and multipotentiality. This is further exacerbated with increased passage numbers in culture, characterized by the onset of senescence related changes. As a consequence, it is necessary to establish protocols for generating large numbers of MSCs but without affecting their differentiation potential. MSCs are capable of differentiating into mesenchymal tissue lineages, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Recent findings indicate that adult bone marrow may also contain cells that can differentiate into the mature, nonhematopoietic cells of a number of tissues, including cells of the liver, kidney, lung, skin, gastrointestinal tract, and myocytes of heart and skeletal muscle. MSCs can readily be expanded in vitro and can be genetically modified by viral vectors and be induced to differentiate into specific cell lineages by changing the microenvironment–properties which makes these cells ideal vehicles for cellular gene therapy. MSCs can also exert profound immunosuppressive effects via modulation of both cellular and innate immune pathways, and this property allows them to overcome the issue of immune rejection. Despite the many attractive features associated with MSCs, there are still many hurdles to overcome before these cells are readily available for use in clinical applications. The main concern relates to in vivo characterization and identification of MSCs. The lack of a universal biomarker, sparse in vivo distribution, and a steady age related decline in their numbers, makes it an obvious need to decipher the reprogramming pathways and critical molecular players which govern the characteristics unique to MSCs. This book presents a comprehensive insight into the biology of adult stem cells and their utility in current regeneration therapies. The adult stem cell populations reviewed in this book include bone marrow derived MSCs, adipose derived stem cells (ASCs), umbilical cord blood stem cells, and placental stem cells. The features such as MSC circulation and trafficking, neuroprotective properties, and the nurturing roles and differentiation potential of multiple lineages have been discussed in details. In terms of therapeutic applications, the strengths of MSCs have been presented and their roles in disease treatments such as osteoarthritis, Huntington’s disease, periodontal regeneration, and pancreatic islet transplantation have been discussed. An analysis comparing osteoblast differentiation of umbilical cord blood stem cells and MSCs has been reviewed, as has a comparison of human placental stem cells and ASCs, in terms of isolation, identification and therapeutic applications of ASC in bone, cartilage regeneration, as well as myocardial regeneration. It is my sincere hope that this book will update the reader as to the research progress of MSC biology and potential use of these cells in clinical applications. It will be the best reward to all contributors of this book, if their efforts herein may in some way help the readers in any part of their study, research, and career development.

Death : is it fatal?

Death is a common occurrence in the world of today and impacts upon families in a variety of ways, depending upon a range of circumstances. This paper examines the impact that a sudden, unexpected death of the founder of a family business had on both the business and the family. The basis for the research is a single case study of a family business operating in regional Victoria. At the time of the death of the family founder (from a fatal motorcycle accident) his adult children had not been prepared to take over the company. The paper examines if the death of the founder proved fatal to the family business.

Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation

KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations. Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2. This cell death in response to FGFR2 inhibition occurred within the context of loss-of-function mutations in PTEN and constitutive AKT phosphorylation, and was associated with a marked reduction in extracellular signal-regulated kinase 1/2 activation. Together, these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2, despite the frequent abrogation of PTEN in this cancer type.

The rules of autogeddon : sex death and law in J G Ballard’s Crash

It was reported that the manuscript of Crash was returned to the publisher with a note reading ‘The author is beyond psychiatric help’. Ballard took the lay diagnosis as proof of complete artistic success. Crash conflates the Freudian tropes of libido and thanatos, overlaying these onto the twentieth century erotic icon, the car. Beyond mere incompetent adolescent copulatory fumblings in the back seat of the parental sedan or the clichéd phallic locomotor of the mid-life Ferrari, Ballard engages the full potentialities of the automobile as the locus and sine qua non of a perverse, though functional erotic. ‘Autoeroticism’ is transformed into automotive, traumatic or surgical paraphilia, driving Helmut Newton’s insipid photo-essays of BDSM and orthopædics into an entirely new dimension, dancing precisely where (but more crucially, because) the ‘body is bruised to pleasure soul’. The serendipity of quotidian accidental collisions is supplanted, in pursuit of the fetishised object, by contrived (though not simulated) recreations of iconographic celebrity deaths. Penetration remains as a guiding trope of sexuality, but it is confounded by a perversity of focus. Such an obsessive pursuit of this autoerotic-as-reality necessitates the rejection of the law of human sexual regulation, requiring the re-interpretation of what constitutes sex itself by looking beyond or through conventional sexuality into Ballard’s paraphiliac and nightmarish consensual Other. This Other allows for (if not demands) the tangled wreckage of a sportscar to function as a transformative sexual agent, creating, of woman, a being of ‘free and perverse sexuality, releasing within its dying chromium and leaking engine-parts, all the deviant possibilities of her sex’.

An accessible method for teaching doctors about death certification

The World Health Organization recommends that data on mortality in its member countries are collected utilising the Medical Certificate of Cause of Death published in the instruction volume of the ICD-10. However, investment in health information processes necessary to promote the use of this certificate and improve mortality information is lacking in many countries. An appeal for support to make improvements has been launched through the Health Metrics Network’s MOVE-IT strategy (Monitoring of Vital Events – Information Technology) [World Health Organization, 2011]. Despite this international spotlight on the need for capture of mortality data and in the use of the ICD-10 to code the data reported on such certificates, there is little cohesion in the way that certifiers of deaths receive instruction in how to complete the death certificate, which is the main source document for mortality statistics. Complete and accurate documentation of the immediate, underlying and contributory causes of death of the decedent on the death certificate is a requirement to produce standardised statistical information and to the ability to produce cause-specific mortality statistics that can be compared between populations and across time. This paper reports on a research project conducted to determine the efficacy and accessibility of the certification module of the WHO’s newly-developed web based training tool for coders and certifiers of deaths. Involving a population of medical students from the Fiji School of Medicine and a pre and post research design, the study entailed completion of death certificates based on vignettes before and after access to the training tool. The ability of the participants to complete the death certificates and analysis of the completeness and specificity of the ICD-10 coding of the reported causes of death were used to measure the effect of the students’ learning from the training tool. The quality of death certificate completion was assessed using a Quality Index before and after the participants accessed the training tool. In addition, the views of the participants about accessibility and use of the training tool were elicited using a supplementary questionnaire. The results of the study demonstrated improvement in the ability of the participants to complete death certificates completely and accurately according to best practice. The training tool was viewed very positively and its implementation in the curriculum for medical students was encouraged. Participants also recommended that interactive discussions to examine the certification exercises would be an advantage.

The Tension between a constructed self and universal reason in considerations of elective death

Review of Coping with Choices to Die, by C. G. Prado. Cambridge: Cambridge University Press, 2011.

When does pain and distress relief hastening death become killing?

This paper discusses the question of when pain and distress relief known to hasten death would cross the line between permissible conduct and killing. The issue is discussed in the context of organ donation after cardiac death, and considers the administration of analgesics, sedatives, and the controversial use of paralysing agents in the provision and withdrawal of ventilation.